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Emerging Role of the Inflammasome and Pyroptosis in Hypertension

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Emerging Role of the Inflammasome and Pyroptosis in Hypertension International Journal of Molecular Sciences Review Emerging Role of the Inflammasome and Pyroptosis in Hypertension Carmen De Miguel 1,* , Pablo Pelegrín 2 , Alberto Baroja-Mazo 2,† and Santiago Cuevas 2,*,† 1 Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA 2 Molecular Inflammation Group, Biomedical Research Institute of Murcia (IMIB-Arrixaca), 30120 Murcia, Spain; [email protected] (P.P.); alberto.baroja@ffis.es (A.B.-M.) * Correspondence: [email protected] (C.D.M.); [email protected] (S.C.); Tel.: +34-868-885031 (S.C.) † co-senior author. Abstract: Inflammasomes are components of the innate immune response that have recently emerged as crucial controllers of tissue homeostasis. In particular, the nucleotide-binding domain, leucine-rich- containing (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is a complex platform involved in the activation of caspase-1 and the maturation of interleukin (IL)-1β and IL-18, which are mainly released via pyroptosis. Pyroptosis is a caspase-1-dependent type of cell death that is mediated by the cleavage of gasdermin D and the subsequent formation of structurally stable pores in the cell membrane. Through these pores formed by gasdermin proteins cytosolic contents are released into the extracellular space and act as damage-associated molecular patterns, which are pro- inflammatory signals. Inflammation is a main contributor to the development of hypertension and it also is known to stimulate fibrosis and end-organ damage. Patients with essential hypertension and animal models of hypertension exhibit elevated levels of circulating IL-1β. Downregulation of the expression of key components of the NLRP3 inflammasome delays the development of hypertension and pharmacological inhibition of this inflammasome leads to reduced blood pressure in animal models and humans. Although the relationship between pyroptosis and hypertension is not well Citation: De Miguel, C.; Pelegrín, P.; established yet, pyroptosis has been associated with renal and cardiovascular diseases, instances Baroja-Mazo, A.; Cuevas, S. Emerging where high blood pressure is a critical risk factor. In this review, we summarize the recent literature Role of the Inflammasome and addressing the role of pyroptosis and the inflammasome in the development of hypertension and Pyroptosis in Hypertension. Int. J. discuss the potential use of approaches targeting this pathway as future anti-hypertensive strategies. Mol. Sci. 2021, 22, 1064. https:// doi.org/10.3390/ijms22031064 Keywords: hypertension; pyroptosis; inflammasome; inflammation Received: 31 December 2020 Accepted: 18 January 2021 Published: 21 January 2021 1. Inflammation and Hypertension Publisher’s Note: MDPI stays neutral Elevated blood pressure, defined as a systolic pressure higher than 130 mmHg and with regard to jurisdictional claims in diastolic pressure greater than 80 mmHg [1], is the leading risk for cardiovascular and published maps and institutional affil- kidney diseases [2] and was reported to affect 1.13 billion people in the world in 2016 [3]. iations. As a consequence, high blood pressure is a leading cause of death worldwide [4] and research in the field of hypertension is highly dynamic. Extensive evidence demonstrates an important role of inflammation in the pathogenesis of hypertension and vascular and kidney diseases. A series of elegant studies performed by Grollman et al. in the 1960s Copyright: © 2021 by the authors. first evidenced that autoimmune factors play a critical role in an animal model of renal Licensee MDPI, Basel, Switzerland. infarction-induced hypertension [5,6]. The same group also reported that hypertension This article is an open access article could be transferred to normotensive rats by transplanting lymph node cells from rats with distributed under the terms and renal infarction hypertension [7]. In the 1970s, Svendsen revealed that an intact thymus conditions of the Creative Commons is required for the maintenance or development of hypertension in three different animal Attribution (CC BY) license (https:// models of the disease: the deoxycorticosterone acetate (DOCA) salt model [8], mice with creativecommons.org/licenses/by/ partially infarcted kidneys [9], and the genetically hypertensive NZB/Cr mouse strain [10]. 4.0/). Int. J. Mol. Sci. 2021, 22, 1064. https://doi.org/10.3390/ijms22031064 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 1064 2 of 21 Since those early studies, investigation of the interplay between inflammation and high blood pressure has grown exponentially, and more than 18,000 publications have explored this topic to date. It is now widely acknowledged that low-grade or persistent inflammation is a key player in the development and maintenance of hypertension. Exhaus- tive research demonstrates the infiltration of immune cells, like T cells, macrophages, and dendritic cells in the kidneys, perivascular fat, or heart during the development and pro- gression of hypertension [11–24]. In particular, immune cell transfer studies performed by Guzik et al. [15] demonstrated that the development of angiotensin II-induced and DOCA salt-induced hypertension was dependent on the presence of T cells. Moreover, pharmaco- logical inhibition of immune cells with, for instance, mycophenolate mofetil, tacrolimus, or cyclophosphamide attenuates the development of high blood pressure [25–29]. More recently, the genetic ablation of certain immune cells and specific receptors on immune cells or cytokines demonstrates that activation of immune cells like T cells, macrophages, and dendritic cells [18,23,30–35] is essential for the development of elevated blood pressure. Lately, B cells have also been reported to be important in the development of hyperten- sion [36]. The role of immune cells from the adaptive and innate arms of the immune response as well as different cytokines in hypertension has been extensively reviewed elsewhere, and thus, we will not review it here [37–42]. As mentioned above, inflammatory cells have been repeatedly demonstrated to in- filtrate organs involved with blood pressure regulation, including the vasculature, the kidneys, and the brain [40,43,44], during hypertension. For instance, in a hypertensive kidney, macrophages and T cells localize around glomeruli and arterioles and within the interstitium [45,46]. Similarly, infiltration of immune cells and increased levels of inflam- matory mediators have been demonstrated in the perivascular fat of large arteries and arterioles in animal models of hypertension [45]. Activated inflammatory cells produce and release cytokines like tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), IL-17, IL-6, and interferon-gamma (IFN-γ) that are known inducers of renal and vascular dys- function [33–35,47–49]. Many of those inflammatory mediators are known to stimulate fibrosis [47,50,51], for instance, which is seen in both vessels and kidneys of hypertensive patients and animal models of the disease. In addition, T cells and macrophages contain all the machinery needed for the production of vasoactive molecules such as angiotensin II [52–54], endothelin-1 [55,56], or prostaglandins [57,58], which are known mediators of hypertension and hypertension-induced end-organ damage. Moreover, a number of inflam- matory factors released by activated immune cells can also modulate the local production of angiotensinogen and, later, angiotensin II generation within the kidneys, vasculature, or nervous system [51,59,60]. This implies that inflammatory cells increase the local levels of pro-hypertensive stimuli and can further increase blood pressure by stimulating fluid retention and vascular constriction [61]. Interesting animal studies have also shown that IL-17 or IFN-γ deficiency is associated with alterations of sodium (Na+) transporters in the kidneys and, consequently, reduced Na+ retention in hypertensive conditions [62]. Despite all this evidence linking immune cell infiltration and the development and progression of hypertension, the exact mechanisms that trigger low-level inflammation observed in the elevated blood pressure setting still remain unclear. 2. Inflammasomes and Pyroptotic Cell Death Inflammasomes are essential players in the inflammatory response and one of the first steps for the initiation of chronic low-grade inflammation. Inflammasomes are intracellular protein oligomers that are sensors for pathogens, tissue injuries, and recognition of the signals altering homeostasis. They are composed of an effector protein, an adaptor protein, and a sensor protein that oligomerize in a large complex after activation. The inflam- masome sensor protein is usually a pattern recognition receptor (PRR) that oligomerizes after activation induced by pathogen-associated molecular patterns (PAMPs), endogenous host-derived damage-associated molecular patterns (DAMPs), or homeostasis-altering molecular processes (HAMPs) [63]. Three families of sensor proteins have been described, Int. J. Mol. Sci. 2021, 22, 1064 3 of 21 belonging to the nucleotide-binding domain, leucine-rich-containing family of receptors (NLRs), the absent in melanoma 2-like receptors (ALRs) or pyrin, which give name to the inflammasome and share analogous structural domains. Moreover, there are several types of inflammasomes, such as NLRP1b (mouse), NLRP3, NLR family CARD domain- containing protein 4 (NLRC4), NLRP6, NLRP9, pyrin, and absent in melanoma (AIM) 2. A great variety of molecules activate
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